Many of the major barriers to applying evidence-based guidelines in complex patients originate from the fact that guidelines are developed for the management of diseases instead of people with diseases. With rare exceptions, guidelines focus on the management of a single disease, or a single disease-problem, and do not address how to optimally integrate care for individuals whose multiple problems may make guideline recommended management of any single disease impractical, irrelevant or even harmful. Current standards of guideline development or appraisal do not prompt guideline developers to address the issue that not all patients benefit similarly from similar therapy (i.e., heterogeneity of treatment effect), nor do they provide tools for adapting the recommendations to the patient with many diseases or prioritizing the most important recommendations within a single disease, let alone between diseases. The root of this problem, however, is not narrowly confined to guideline development and application, but is inherent throughout the translational path from the generation of the evidence to the synthesis of the evidence upon which guidelines depend. Indeed, complex patients with multimorbidity are frequently excluded from the relevant clinical trials. And even where such patients are not explicitly excluded, it can be difficult to know whether the summary result of a trial apply to an individual with multimorbidity, since a trial's overall results may not reflect all patients in the trial equally, and how to make "average" trial results more applicable to specific individuals, or particular groups, such as complex patients with more competing risks than average, has not been fully resolved. Thus, at multiple levels including trial design and analysis, the synthesis of trial results in meta-analyses and systematic reviews, and the guideline development process, the very information necessary to support evidence-based care of the complex patient is excluded. Needed, then, is a comprehensive approach built on a firm understanding of each of these phases of evidence development and implementation. We have, therefore, assembled a collaborative team with complementary expertise spanning these various levels, and a special interest in the complex patient, to develop a comprehensive description of the problem and, ultimately, a prioritized set of recommendations to inform each stage of the process of generating evidence-based guidance for the complex patient.